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Regulation of nuclear factor-kappa B, activator protein-1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells.

Abstract：

:The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox-sensitive transcription factors such as nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), which regulate the genes for proinflammatory mediators and protective antioxidant genes. GSH, a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant against oxidative stress, which plays a key role in the control of proinflammatory processes in the lungs. The rate-limiting enzyme in GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS), which consists of a catalytic heavy and a regulatory light subunit. The promoter regions of the human gamma-GCS subunits contain AP-1, NF-kappa B, and antioxidant response elements and are regulated by oxidants, growth factors, inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory agent (dexamethasone) in lung cells. TNF-alpha depletes intracellular GSH, concomitant with an increase in oxidised glutathione levels in alveolar epithelial cells. TNF-alpha also induces the activation of NF-kappa B and AP-1 and the subsequent increase in gamma-GCS heavy subunit transcription in these cells. Dexamethasone depleted both basal and TNF-alpha-stimulated GSH levels by down-regulating the gamma-GCS-heavy subunit transcription via a mechanism involving AP-1 (c-Jun). The existence of this fine tuning between the redox GSH levels and the activation of transcription factors may determine the balance of transcription for proinflammatory and antioxidant gamma-GCS genes in inflammation. More studies are required to understand the signalling mechanism of the redox regulation of NF-kappa B and AP-1 and gene transcription in inflammation. This could lead to the development of therapeutic strategies based on the pharmacological manipulation of the production of this important antioxidant in inflammation.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Rahman I

doi

10.1016/s0006-2952(00)00392-0

subject

Has Abstract

pub_date

2000-10-15 00:00:00

pages

1041-9

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(00)00392-0

journal_volume

pub_type

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Regulation of nuclear factor-kappa B, activator protein-1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells.